Value of GCET1, HGAL (GCET2), and LMO2 in the Determination of Germinal Center Phenotype in Diffuse Large B-cell Lymphoma

Turk J Haematol. 2023 Aug 31;40(3):162-173. doi: 10.4274/tjh.galenos.2023.2023.0110. Epub 2023 Jul 31.

Abstract
in English, Turkish

Objective: Diffuse large B-cell lymphoma (DLBCL) is a biologically heterogeneous disease that is classified into germinal center B-cell (GCB) and non-GCB subtypes, which are prognostically different. The Hans algorithm is the most widely used tool based on CD10, BCL6, and MUM1 expression, but some cases with the non-GCB phenotype are still known to be misclassified. In this study, we investigate the extent to which GCET1, HGAL, and LMO2 protein expressions reflect GCB phenotype together with their roles in determining the GCB phenotype of DLBCL and their contributions to the performance of the Hans algorithm.

Materials and methods: Sixty-five cases of DLBCL-not otherwise specified, 40 cases of follicular lymphoma (FL), and 19 non-GC-derived lymphoma cases were included in this study. The DLBCL cases were grouped as CD10+ (Group A) or only MUM1+ (Group B), and the remaining cases constituted the intermediate group (Group C). GCET1, HGAL, and LMO2 expressions were evaluated.

Results: In the FL group, GCET1, HGAL, and LMO2 were positive in 85%, 77.5%, and 100% of the cases, respectively. Among the non-GC-derived lymphoma cases, all three markers were negative in cases of small lymphocytic lymphoma, plasmablastic lymphoma, peripheral T-cell lymphoma, and anaplastic large cell lymphoma. GCET1 and HGAL were negative in cases of marginal zone lymphoma (MZL) and mantle cell lymphoma (MCL). Two of the 3 MZL and 2 of the 4 MCL cases were positive for LMO2. In the DLBCL group, the number of cases with GCET1, HGAL, and LMO2 positivity was 18 (90%), 17 (85%), and 20 (100%), respectively, in Group A and 0 (0%), 2 (13.3%), and 2 (13.3%), respectively, in Group B. Considering these rates, when the cases in the intermediate group were evaluated, it was concluded that 13 cases typed as non-GCB according to the Hans algorithm may have the GCB phenotype.

Conclusion: GCET1, HGAL, and LMO2 are highly sensitive markers for determining the germinal center cell phenotype and can increase the accuracy of the subclassification of DLBCL cases, especially for cases that are negative for CD10.

Amaç: Diffüz büyük B-hücreli lenfoma (DBBHL), germinal merkez B (GMB) hücre ve non-GMB hücre olmak üzere prognostik olarak farklı alt grupları olan biyolojik olarak heterojen bir hastalıktır. CD10, BCL6 ve MUM1 ekspresyonuna göre yapılan Hans algoritması ile GMB olgularının bazıları yanlış sınıflandırılmaktadır. Çalışmamızda, immünohistokimyasal olarak GMB hücre belirteçleri olan GCET1, HGAL ve LMO2’nin folikül merkez hücre fenotipini ne derecede yansıttığını, DBBHL’de GMB hücre fenotipini belirlemedeki rolünü ve Hans algoritmasına katkısını araştırmaktayız.

Gereç ve yöntemler: Altmış beş adet DBBHL-NOS, 40 adet foliküler lenfoma (FL) ve 19 adet non-GM kökenli lenfoma olgusu çalışmaya alındı. DBBHL olguları CD10+ (Grup A), sadece MUM1+ (Grup B) ve kalanlar ara grup (Grup C) olarak gruplandı. GCET1, HGAL ve LMO2 ekspresyonları değerlendirildi.

Bulgular: FL grubunda, GCET1, HGAL ve LMO2 sırasıyla %85, %77,5, %100 olguda pozitif saptandı. Küçük lenfositik lenfoma, plazmablastik lenfoma, periferik T-hücreli lenfoma ve anaplastik büyük hücreli lenfoma olgularında 3 antikor da negatifti. Marjinal zon lenfoma (MZL) ve mantle hücreli lenfoma (MHL) olgularında GCET1 ve HGAL negatifken; LMO2, 2 MZL ve 2 MHL’de pozitif bulundu. DBBHL olgularında, Grup A’da GCET1, HGAL and LMO2 pozitif olgu sayısı sırasıyla 18 (%90), 17 (%85), 20 (%100) iken, Grup B’de sırasıyla 0 (%0), 2 (%13,3), 2 (%13,3) idi (p<0,001). Bu oranlar göz önüne alınarak ara gruptaki olgular değerlendirildiğinde, Hans algoritmasına göre non-GMB olarak tiplendirilen 13 olgunun GMB fenotipli olabileceği sonucuna varıldı.

Sonuç: GCET1, HGAL ve LMO2, GMB fenotipini belirlemede duyarlı belirteçler olup, DBBHL’lerin (özellikle CD10 negatif olguların) doğru tiplendirilmesine katkı sağladıkları düşünülmüştür.

Keywords: Diffuse large B-cell lymphoma; Immunohistochemistry; GCET1; GCET2 (HGAL); LMO2; Hans algorithm.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Adult
  • Germinal Center / metabolism
  • Germinal Center / pathology
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • LIM Domain Proteins / genetics
  • LIM Domain Proteins / metabolism
  • Lymphoma, Follicular* / pathology
  • Lymphoma, Large B-Cell, Diffuse* / genetics
  • Neoplasm Proteins / genetics
  • Phenotype
  • Proto-Oncogene Proteins / genetics

Substances

  • Adaptor Proteins, Signal Transducing
  • Intracellular Signaling Peptides and Proteins
  • LIM Domain Proteins
  • LMO2 protein, human
  • Neoplasm Proteins
  • Proto-Oncogene Proteins
  • SERPINA9 protein, human
  • GCSAM protein, human